Intermediates in the preparation of 4-phenylpyrrole derivatives

ABSTRACT

The invention relates to a process for the preparation of 4-phenylpyrrole derivatives of the formula I ##STR1## wherein R n , R 1  and R 2  are as defined in claim 1, which comprises reacting a phenacylamine of formula II ##STR2## with a compound of formula III 
     
         T--CH═CH--R.sub.1                                      (III) 
    
     to give an intermediate of formula IV ##STR3## and cyclizing said intermediate, in the presence of a base, to give the compound I. 
     Important intermediates and novel final products are also described.

This is a divisional of application Ser. No. 093,449 filed on Sept. 4,1987, now U.S. Pat. No. 4,812,580, which is a divisional of applicationSer. No. 773,706, filed on Sept. 9, 1985, now U.S. Pat. No. 4,709,053.

The present invention relates to a novel process for the preparation of4-phenylpyrrole derivatives of the formula I ##STR4## wherein R₁ is CN,CHO or COO(C₁ -C₆)alkyl, R₂ is hydrogen, CH₂ CH₂ CN or CH₂ CH₂ COO(C₁-C₆)alkyl, R is halogen, C₁ -C₆ alkyl or C₁ -C₆ haloalkyl, and n is 0, 1or 2.

Depending on the indicated number of carbon atoms, alkyl by itself or asmoiety of another substituent, such as haloalkyl and the like, comprisese.g. the following straight chain or branched groups: methyl, ethyl,propyl, butyl, pentyl, hexyl etc., and the isomers thereof, e.g.isopropyl, isobutyl, tert-butyl, isopentyl etc. Throughout thisspecification, a substituent prefixed by "halo" will be understood asmeaning that said substituent may be monohalogenated or perhalogenated.Halogen and halo signify in particular fluorine, chlorine or bromine.Hence haloalkyl denotes a monohalogenated to perhalogenated alkylradical, e.g. CHCl₂, CH₂ F, CCl₃, CH₂ Cl, CHF₂, CH₂ CH₂ Br, C₂ Cl₅,CHBr, CHBrCl etc., with CF₃ being preferred.

4-Phenylpyrrole derivatives of formula I, wherein n is 0, 1 or 2, R₁ iscyano and R₂ is hydrogen or acetyl, are known as plant fungicides fromGerman Offenlegungsschrift No. 29 27 480.sup.(1). As will be shownbelow, compounds of formula I, wherein R₁ is CHO or COO(C₁ -C₆)alkyl orR₂ is CH₂ CH₂ CN or CH₂ CH₂ COO(C₁ -C₆)alkyl, can be converted in simplemanner into the known fungicidal 4-phenyl-3-cyanopyrroles and thus havethe character of intermediates.

A process for the preparation of 4-phenyl-3-cyanopyrrole derivativeswhich is known from Tetrahedron Letters No. 52, pp. 5337-5340,1972.sup.(2), is disclosed in German Offenlegungsschrift No. 29 27480.sup.(1). In this process, known as the TosMIC process, a cinnamicacid derivative of formula X ##STR5## is cyclised with tosyl methylisocyanide (XX) [TosMIC], in the presence of a strong base, e.g. sodiumhydride, to give 4-phenyl-3-cyanopyrrole derivatives of formula (XXX).In the above formulae, R is as defined for formula I and n is 0, 1 or 2.

Although numerous pyrrole syntheses are known (q.v. J. M. Patterson,Synthesis 1976, pp. 281-304.sup.(3)), only the TosMIC process outlinedabove has so far led direct to the fungicidally useful4-phenyl-3-cyanopyrrole derivatives. However, reference (2) indicatesfor the preparation of 4-phenyl-3-cyanopyrrole a yield of only 35%,which is low for industrial purposes. It has been found that the reagentTosMIC has grave disadvantages for industrial syntheses. For example, atelevated temperatures above 90° C. (normal drying conditions), TosMIChas the propensity to decompose explosively. On the other hand, residualmoisture consumes some of the base employed (danger ofhydrolysis/reduction in yield). Further, TosMIC has physiologicalhazards and causes severe irritation to the eyes and skin.

The shortcomings referred to above show that useful laboratory methodsare unsuitable for the industrial production of 4-phenylpyrrolederivatives. A novel, more economic and environmentally more acceptableprocess for the preparation of these compounds in surprisingly highyield has now been found.

The novel process of this invention for the preparation of the4-phenylpyrrole derivatives of the formula I as defined at the outsetcomprises reacting a phenacylamine of formula II ##STR6## in the form ofan acid addition salt, with a compound of formula III

    T--CH═CH--R.sub.1                                      (III)

to give an intermediate of formula IV ##STR7## and cyclising thiscompound of formula IV, in the presence of a base, to a compound offormula I. In the formulae II, III and IV above, the substituents R₁, R₂and R_(n) are as defined for formula I, T is a group selected from --OZ,--N(R₃)(R₄), --OCOR_(a), --OSO₂ R_(b), --SR_(c) or halogen, where Z isC₁ -C₆ alkyl, unsubstituted or substituted phenyl, an alkali metal atomor an alkaline earth metal atom, each of R_(a) and R_(b) independentlyof the other is C₁ -C₆ alkyl or unsubstituted or substituted phenyl,R_(c) is C₁ -C₃ alkyl, C₁ -C₃ haloalkyl or unsubstituted or substitutedphenyl; and each of R₃ and R₄ independently of the other is C₁ -C₆ alkylor, together with the amine nitrogen atom, form a saturated 5- or6-membered heterocyclic ring which contains, as hetero atom, either onlythe amine nitrogen atom or a further hetero atom.

An unsubstituted or substituted phenyl group is in particular phenyl orphenyl which is substituted in the para-position by halogen, preferablychlorine or bromine, and by C₁ -C₃ alkyl, preferably methyl. Alkalimetal atoms or alkaline earth metal atoms may be Li, Na and K,preferably Na and K, or Mg, Ca, Sr and Ba, preferably Mg, Ca and Ba.Where the --N(R₃)(R₄) group denotes a saturated 5- or 6-memberedheterocyclic ring containing N as hetero atom or a further hetero atom,said ring may be selected from the following heterocyclic ring systems:pyrrolidine, piperazine, perhydrothiazine, morpholine, piperazine,oxazolidine, thiazolidine, imidazolidine, pyrazoline and the like. Afurther hetero atom is preferably N, O or S.

In the process of this invention it is not necessary to isolate theintermediate (IV) first and then to cyclise it to compounds of formulaI. To the contrary, the reaction of (II) with (III) may also be carriedout direct in the presence of a base, utilising a single reaction vesselfor both steps, to give the final products. In this procedure, theintermediate (IV) is further processed direct without isolation. On theother hand, it may be convenient to prepare the intermediate (IV) firstin especially pure form, e.g. by repeated recrystallisation, and then tocyclise it to a compound of formula I. A preferred embodiment of theprocess of this invention accordingly comprises reacting thephenacylamine II in the form of an acid addition salt, in the presenceof a base, direct with a compound of formula III to give the finalproduct I.

The second preferred embodiment of the process comprises first reactingthe phenacylamine II in the form of an acid addition salt, in theabsence of a base, to give the intermediate (IV) and then converting(IV) to (I) by cyclisation in the presence of a base.

The reactants (II), (III) and, where appropriate, (IV), are convenientlyemployed in equimolar amounts. It is preferred to add an equimolaramount or an excess of base.

Typical representatives of the compounds of formula III, the list ofwhich is not exhaustive, are the following compounds (a) to (t), ofwhich compounds (a) to (l) are particularly advantageous and thereforepreferred:

(a) (CH₃)₂ N--CH═CH--CN

(b) (C₂ H₅)₂ N--CH═CH--CN

(c) ##STR8## (d) ##STR9## (e) ##STR10## (f) NaO--CH═CH--CN (g)KO--CH═CH--CN

(h) (CH₃)₂ N--CH═CH--COOCH₃

(i) (C₂ H₅)₂ N--CH═CH--COOCH₃

(k) (CH₃)₂ N--CH═CH--CHO

(l) (C₂ H₅)₂ N--CH═CH--CHO

(m) Cl--CH═CH--CN

(n) Cl--CH═CH--COOCH₃

(o) CH₃ O₂ SO--CH═CH--CN

(p) [C₆ H₄ CH₃ (4)]--CH═CH--CN

(q) CH₃ O--CH═CH--CN

(r) C₂ H₅ O--CH═CH--CN

(s) C₃ H₇ O--CH═CH--CN

(t) [C₆ H₄ Cl(4)]O--CH═CH--COOCH₃

The process of this invention is conveniently carried out in an inertsolvent or mixture of solvents. Thus one or more inert solvents ordiluents may be employed. Examples of suitable solvents and diluentsare: aliphatic and aromatic hydrocarbons such as benzene, toluene,xylenes, petroleum ether; halogenated hydrocarbons such aschlorobenzene, methylene chloride, ethylene chloride, chloroform, carbontetrachloride, tetrachloroethylene; ethers and ethereal compounds suchas dialkyl ethers (diethyl ether, diisopropyl ether, tert-butylmethylether etc.), anisole, dioxane, tetrahydrofuran; nitriles such asacetonitrile and propionitrile; N,N-dialkylated amides such asdimethylformamide; dimethylsulfoxide; ketones such as acetone, diethylketone, methyl ethyl ketone; alcohols, in particular methanol, ethanol,propanols, butanols and the like; and water and aqueous two-phasemixtures and mixtures of the above solvents.

The following solvents for example are suitable for the organicwater-immiscible phase: aliphatic and aromatic hydrocarbons such aspentane, xylenes etc.; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, ethylene dichloride,1,2-dichloroethane, tetrachloroethylene and the like, or aliphaticethers such as diethyl ether, diisopropyl ether, tert-butylmethyl etherand the like. The addition of a phase transfer catalyst may beadvantageous. Examples of suitable phase transfer catalysts are:tetraalkylammonium halides, hydrogen sulfates or hydroxides, e.g.tetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, triethylbenzylammonium chloride ortriethylbenzylammonium bromide, tetrapropylammonium chloride,tetrapropylammonium bromide or tetrapropylammonium iodide etc. Suitablephase transfer catalysts are also phosphonium salts. The ammonium saltof formula II itself acts as phase transfer catalyst.

Particularly suitable solvents are nitriles and lower alkanols,preferably acetonitrile and ethanol, as well as mixtures ofalkanol/water (ethanol/water).

In all partial steps and in the single vessel reaction, the reactiontemperatures are generally in the range from 0° to +120° C., preferablyfrom +30° to +80° C.

Owing to the reduced thermal stability of the starting phenacylamine,the compound of formula II is employed in the form of its more stableammonium salt, which can be obtained by conventional addition of anorganic or inorganic acid to the free amine.

Examples of salt-forming acids are inorganic acids, e.g. hydrohalicacids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid orhydriodic acid, as well as sulfuric acid, phosphoric acid, phosphorousacid, nitric acid and the like; and organic acids such as acetic acid,trifluoroacetic acid, trichloroacetic acid, propionic acid, glycollicacid, lactic acid, succinic acid, benzoic acid, cinnamic acid, oxalicacid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, salicyclic acid, 2-phenoxybenzoic acid or2-acetoxybenzoic acid and the like.

Preferred salt-forming acids are strong acids such as the hydrohalicacids, phosphoric acid, nitric acid, and the sulfonic acids such asp-toluenesulfonic acid. Hydrochloric acid is especially preferred.

The reaction of (II) with (III) direct to give (I), or of (IV) to give(I), is conducted in the presence of a base. Examples of suitable basesare inorganic bases such as the oxides, hydrides, hydroxides,carbonates, carboxylic acid salts and alcoholates of alkaline earthmetals, preferably of alkali metals, in particular of sodium andpotassium [e.g. NaH, NaOH, KOH, Na₂ CO₃, K₂ CO₃, CaCO₃, CH₃ COONa, C₂ H₅COOK, C₂ H₅ ONa, CH₃ ONa and the like], preferably the alkali metalalcoholates such as sodium ethylate or sodium methylate. Suitableorganic bases are e.g. triethylamine, piperidine, pyridine,4-dimethylaminopyridine and the like.

In the processes of this invention, intermediates and final products maybe isolated from the reaction medium and, if desired, purified by one ofthe commonly employed methods, for example by extraction,crystallisation, chromatography, distillation and the like. However, thepreparation of the compounds of formula I can be carried out generallyin good yield and in excellent purity utilising a single vessel for bothreaction steps without isolation of intermediates.

Preferred embodiments of the process of this invention are e.g. thosewhich comprise:

(a) the use of starting materials of formula II, wherein R is halogen,preferably fluorine, chlorine or bromine, most preferably chlorine, n is1 or preferably 2, with the proviso that, if n is 2, the ortho- andmeta-positions are particularly preferred, R₁ is CN and R₂ is hydrogen;

(b) the use of reagents of formula III, wherein T is a group selectedfrom --N(CH₃)₂, --N(C₂ H₅)₂, ##STR11## --OK or --ONa, and R₁ is CN,COOCH₃ or CHO, preferably CN; (c) the use of intermediates of formulaIV, wherein R₁, R₂ and R_(n) are as defined in (a) and (b) above;

(d) the use of acid addition salts of formula II, which contain, as acidcomponent, a hydrohalic acid, preferably hydrochloric acid, a sulfonicacid, preferably benzenesulfonic or p-toluenesulfonic acid, or sulfuricacid;

(e) carrying out the reaction of (II) with (III) such that theintermediate IV is further processed direct without isolation;

(f) carrying out the process in the temperature range from +30° to +80°C.

Accordingly, a particularly preferred embodiment of the process of theinvention comprises reacting 2,3-dichlorophenacylamine in the form of anacid addition salt, preferably in the form of the hydrochloride, with acompound of formula III, wherein R₁ is CN and T is a group selected from--N(CH₃)₂, --N(C₂ H₅)₂, ##STR12## --OK or --ONa, preferably --N(CH₃)₂,##STR13## to give 3-(2,3-dichlorophenacylamino)acrylonitrile, andcyclising this intermediate, either as substance or preferably in situ,in the presence of a base, preferably of a lower alkanolate, sodiumhydroxide, potassium hydroxide, sodium acetate, potassium acetate or atri-lower alkylamine, to give 4-(2,3-dichlorophenyl)-3-cyanopyrrole.

Most of the starting materials of formula II are known or can beprepared in similar manner to the known representatives. However,2,3-dichlorophenacylamine and the acid addition salts thereof are novel.In view of its structure, this compound is destined for use asintermediate for the preparation of fungicidally active4-(2,3-dichlorophenyl)-3-cyanopyrrole and therefore constitutes anobject of this invention. Its preparation will be described explicitlybelow.

Compounds of formula II, wherein R₂ is CH₂ CH₂ CN or CH₂ CH₂ COO(C₁-C₆)alkyl, can be prepared e.g. as follows from the startingphenacylamines (II) (R₂ =H): The acid addition salt (e.g. the HCl salt)of an N-substituted phenacylamine of formula II is reacted, in thepresence of an equimolar amount of acrylonitrile or of a C₁ -C₆ alkylester of acrylic acid, preferably in the presence of one of the basesspecified above and under the conditions for the reaction of (II), with(III) to give (I).

Within the scope of the present invention, typical representatives ofcompounds of formula I are for example the compounds listed in Table 1.

                  TABLE 1                                                         ______________________________________                                        Compounds of formula II                                                        ##STR14##                    (II)                                            Compound     R.sub.n R.sub.2                                                  ______________________________________                                        1.1          H       H                                                        1.2          3-Cl    H                                                        1.3          2,4-Cl.sub.2                                                                          H                                                        1.4          4-Cl    H                                                        1.5          4-F     H                                                        1.6          3-CH.sub.3                                                                            H                                                        1.7          3-F     H                                                        1.8          3-Br    H                                                        1.9          3-CF.sub.3                                                                            H                                                        1.10         2-Cl    H                                                        1.11         2,3-Cl.sub.2                                                                          H                                                        1.12         2,5-Cl.sub.2                                                                          H                                                        1.13         2-Br    H                                                        1.14         2,6-Cl.sub.2                                                                          H                                                        1.15         H       CH.sub.2 CH.sub.2 CN                                     1.16         3-Cl    CH.sub.2 CH.sub.2 CN                                     1.17         2-Cl    CH.sub.2 CH.sub.2 CN                                     1.18         2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 CN                                     1.19         3-F     CH.sub.2 CH.sub.2 CN                                     1.20         3-Cl    CH.sub.2 CH.sub.2 COOCH.sub.3                            1.21         2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOCH.sub.3                            1.22         2-Cl    CH.sub.2 CH.sub.2 COOCH.sub.3                            1.23         2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                     1.24         2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOC.sub.3 H.sub.7                     1.25         2-Br    CH.sub.2 CH.sub.2 COOCH.sub.3                            ______________________________________                                    

The compounds of formula III are in general commercially available andthus known substances or compounds which can be prepared in similarmanner to their known representatives.

The preparation of the intermediates of formula IV is an object of thepresent invention and has been described in detail above. Theseintermediates IV can be converted by simple basic cyclisation into theuseful fungicides of formula I, have themselves fungicidal activity, andaccordingly constitute an essential object of the present invention.

Within the scope of this invention, typical representatives ofintermediates of formula IV are:

                  TABLE 2                                                         ______________________________________                                        Compounds of the formula                                                       ##STR15##                    (IV)                                            Compound   R.sub.n R.sub.2       R.sub.1                                      ______________________________________                                        2.1        H       H             CN                                           2.2        3-Cl    H             CN                                           2.3        2,4-Cl  H             CN                                           2.4        4-Cl    H             CN                                           2.5        4-F     H             CN                                           2.6        3-CH.sub.3                                                                            H             CN                                           2.7        3-F     H             CN                                           2.8        3-Br    H             CN                                           2.9        3-CF.sub.3                                                                            H             CN                                           2.10       2-Cl    H             CN                                           2.11       2,3-Cl.sub.2                                                                          H             CN                                           2.12       2,5-Cl.sub.2                                                                          H             CN                                           2.13       2-Br    H             CN                                           2.14       2,6-Cl.sub.2                                                                          H             CN                                           2.15       2,3-Cl.sub.2                                                                          H             COOCH.sub.3                                  2.16       H       H             CHO                                          2.17       3-Cl    H             COOCH.sub.3                                  2.18       3,4-Cl.sub.2                                                                          H             COOCH.sub.3                                  2.19       2-Cl    H             COOCH.sub.3                                  2.20       2,3-Cl.sub.2                                                                          H             COOC.sub.3 H.sub.7                           2.21       2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOCH.sub.3                                                               CN                                           2.22       2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 CN                                                                        CN                                           2.23       H       CH.sub.2 CH.sub.2 CN                                                                        CN                                           2.24       3-Cl    CH.sub.2 CH.sub.2 CN                                                                        CN                                           2.25       2-Cl    CH.sub.2 CH.sub.2 CN                                                                        CN                                           2.26       2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOOC.sub.2 H.sub.5                                                       CN                                           2.27       3-F     CH.sub.2 CH.sub.2 CN                                                                        CN                                           2.28       3-Cl    CH.sub.2 CH.sub.2 COOCH.sub.3                                                               CN                                           2.29       2-Cl    CH.sub.2 CH.sub.2 COOCH.sub.3                                                               CN                                           2.30       2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 COOC.sub.3 H.sub.7                                                        CN                                           2.31       2-Br    CH.sub.2 CH.sub.2 COOCH.sub.3                                                               CN                                           2.32       2,3-Cl.sub.2                                                                          CH.sub.2 CH.sub.2 CN                                                                        CHO                                          ______________________________________                                    

As mentioned at the outset, some of the compounds of formula I have thecharacter of intermediates. These compounds are the representatives offormula I hereinafter referred to as subgroup Ia, wherein R_(n) is asdefined for formula I; and in those compounds in which R₁ is CHO orCOO(C₁ -C₆)alkyl, R₂ is at the same time hydrogen, CH₂ CH₂ CN or CH₂ CH₂COO(C₁ -C₆)alkyl, or in those compounds in which R₁ is CN, R₂ is at thesame time CH₂ CH₂ CN or CH₂ CH₂ COO(C₁ -C₆)alkyl. These novel pyrrolederivatives, which also have fungicidal properties, can be converted insimple manner into the fungicidal 4-phenyl-3-cyanopyrroles known fromGerman Offenlegungsschrift No. 29 27 480, as CHO and COO(C₁ -C₆)alkylcan be converted into CN, and CH₂ CH₂ CN and CH₂ CH₂ COO(C₁ -C₆)alkyl assubstituents at the pyrrole nitrogen atom are easily removable groups.On account of these advantageous properties, the compounds of subgroupIa constitute a further object of the present invention.

Typical examples of compounds of subgroup Ia are listed below.

                  TABLE 3                                                         ______________________________________                                        Compounds of formula Ia                                                        ##STR16##                    (Ia)                                            Compound   R.sub.n R.sub.1   R.sub.2                                          ______________________________________                                        3.1        H       CHO       H                                                3.2        3-Cl    CHO       H                                                3.3        2,4-Cl.sub.2                                                                          CHO       H                                                3.4        4-Cl    CHO       H                                                3.5        4-F     CHO       H                                                3.6        3-CH.sub.3                                                                            CHO       H                                                3.7        3-F     CHO       H                                                3.8        3-CF.sub.3                                                                            CHO       H                                                3.9        2,3-Cl.sub.2                                                                          CHO       H                                                3.10       2,6-Cl.sub.2                                                                          CHO       H                                                3.12       3-Cl    COOCH.sub.3                                                                             H                                                3.13       2-Cl    COOCH.sub.3                                                                             H                                                3.14       4-F     COOCH.sub.3                                                                             H                                                3.15       2,3-Cl.sub.2                                                                          COOCH.sub.3                                                                             H                                                3.16       3-Cl    CN        CH.sub.2 CH.sub.2 CN                             3.17       2-Cl    CN        CH.sub.2 CH.sub.2 CN                             3.18       3-CH.sub.3                                                                            CN        CH.sub.2 CH.sub.2 CN                             3.19       2,3-Cl.sub.2                                                                          CN        CH.sub.2 CH.sub.2 CN                             3.20       4-F     CN        CH.sub.2 CH.sub.2 COOCH.sub.3                    3.21       2-Cl    CN        CH.sub.2 CH.sub.2 COOCH.sub.3                    3.22       2,3-Cl.sub.2                                                                          CN        CH.sub.2 CH.sub.2 COOCH.sub.3                    3.23       2,3-Cl.sub.2                                                                          CHO       CH.sub.2 CH.sub.2 COOCH.sub.3                    3.24       2,3-Cl.sub.2                                                                          COOCH.sub.3                                                                             CH.sub.2 CH.sub.2 CN                             ______________________________________                                    

The conversion of CHO into CN can be effected in a manner known per se,for example as follows: An aldehyde of formula I (R₁ =CHO) is convertedat 0° to 100° C., in an inert solvent (e.g. an alcohol, an ether,pyridine, triethylamine and the like) into the corresponding oxime(syn/anti mixture), which is converted into the nitrile by treatmentwith a dehydrating agent (e.g. acetic anhydride, cyanuricchloride/pyridine, (PNCl₂)₃, dicyclohexyldicarbodiimide/CuCl₂/triethylamine, P₂ O₅, tosyl chloride/pyridine, TiCl₄ /pyridine and thelike).

If it is desired to convert the ester group COO(C₁ -C₆)alkyl into the CNgroup, a start is best made from the free acid, which is prepared in amanner known per se by ester hydrolysis with an aqueous mineral acid(e.g. HCl/H₂ O), in the presence of a solubiliser (e.g. alcohol,dioxane, tetrahydrofuran and the like), most conveniently under refluxtemperature. The free acid is then converted into the acid amide eitherdirect with ammonia at elevated temperature or via the acid chloride(--COOH+thionyl chloride→--COCl) with ammonia at room temperature, andthe acid amide is converted to the nitrile with one of the previouslymentioned dehydrating agents in the temperature range from 80° to 220°C.

If it is desired to form the free pyrrole by removal of the CH₂ CH₂ CNor CH₂ CH₂ COO(C₁ -C₆)alkyl radical, this may be done e.g. by treatmentwith a base in the temperature range from -20° to +180° C., in asuitable inert solvent. Exemplary of suitable reaction conditions are:

(a) sodium hydride in dimethylformamide at 0° C.

(b) ammonia/water/dioxane at 180° C.

(c) potassium hydroxide/water/alcohol at 100° C.

PREPARATORY EXAMPLES Example P1 Preparation of ##STR17##4-(2,3-Dichlorphenyl)-3-cyanopyrrole (a) Preparation of the precursor:N-acetyl-2,3-dichlorophenacylamine

150 g of 2,3-dichlorobenzoyl chloride are hydrogenated with elementalhydrogen under normal pressure at 70° C. in 1.5 l of glacial acetic acidand 84.15 g of acetic anhydride over 5 g of PtO₂. After absorption of112% of the calculated amount of hydrogen (time taken: c. 5 hours), thehydrogenation is discontinued, the reaction mixture is filtered and thefiltrate is concentrated by evaporation. The residual yellow oil iscrystallised by addition of hexane/diethyl ether. The crystallineproduct is isolated by filtration and dried. M.p. 107°-109° C. IR(solid/KBr) in cm⁻¹ : 3300 (NH); 1735 (CO); 1650 (CO). ¹ H-NMR (CDCl₃)in ppm: 2.08 (s, 3H); 4.55 (d, 2H); 6.2-6.6 (broad s, 1H); 7.25 (m, 3H).

(b) Preparation of the precursor: 2,3-dichlorophenacylaminehydrochloride

50.0 g of the N-acetyl-2,3-dichlorophenacylamine obtained in (a) areheated for 2 hours under reflux in 500 ml of hydrochloric acid. Theslightly turbid reaction solution is concentrated by evaporation and theresidue is digested with ethyl acetate. The crystalline2,3-dichlorophenacylamine hydrochloride is isolated by filtration anddried. Melting point: 217°-218° C. IR (solid/KBr) in cm⁻¹ : 1695 (CO).(Another crystal modification shows two carbonyl resonance bands at 1690and 1705 cm⁻¹). ¹ H-NMR (DMSO, d6) in ppm: 4.54 (s, 2H); 7.6 (t, 1H);7.9 (m, 2H); 8.6 (s, 3H, replaceable with D₂ O).

(c) Preparation of the final product4-(2,3-dichlorophenyl)-3-cyanopyrrole

20.0 g of 2,3-dichlorophencylamine hydrochloride and 10.0 g of3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300ml of ethanol. Then an ethanolic solution of sodium ethylate, preparedfrom 2.1 g of sodium and 30 ml of ethanol, is rapidly added dropwise andthe reaction mixture is stirred for another 10 minutes under reflux. Thereaction mixture is cooled to room temperature and then poured intoice/hydrochloric acid and the resultant mixture is stirred for 11/2hours. The precipitate is isolated by filtration, washed with water anddried, affording 15.4 g (78% of theory) of title compound with a meltingpoint of 152°-154° C.

Examples P2 to P4 Preparation of ##STR18##4-(2,3-Dichlorophenyl)-3-cyanopyrrole

Following the procedure described in Example P1c), but replacing3-dimethylaminoacrylonitrile by

N-piperidinylacrylonitrile,

N-pyrrolidinylacrylonitrile, or

N-morpholinylacrylonitrile,

and increasing the reaction time from 1 hour to 3 to 4 hours, pure4-(2,3-dichlorophenyl)-3-cyanopyrrole is obtained in all three Examplesin yields ranging from 76 to 85% of theory. Melting point: 150°-154° C.

Example P5 Preparation of ##STR19##4-(2,3-dichlorophenyl)-3-cyanopyrrole (a) Preparation of theintermediate: 3-(2,3-dichlorophenacylamino)acrylonitrile

20.0 g of 2,3-dichlorophenacylamine hydrochloride and 10.0 g of3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300ml of ethanol. After cooling it to room temperature, the reactionsolution is poured into a mixture of ice/dilute hydrochloric acid. Afterextraction with ethyl acetate, the combined extracts are dried oversodium sulfate, filtered, and the filtrate is concentrated. The oilyresidue is purified by column chromatography (silica gel: elution with a4:1 mixture of toluene/ethyl acetate). M.p. 125°-127° C. IR (solid/KBr)in cm⁻¹ : 3380 (NH), 2200 (CN), 1715 (CO) 1625 (C═C). ¹ H-NMR(DMSO_(d6)) in ppm: 4.09 (d, J=15 Hz, 1H); 4.46 (d, J=7 Hz, 2H); 7.2 (q,1H); 7.4 (broad s, 1H); 7.45-7.85 (m, 3H). Mass spectrum: molecular peakat 254.

(b) Preparation of the final product4-(2,3-dichlorophenyl)-3-cyanopyrrole

To 4.2 g of the 3-(2,3-dichlorophenacylamino)acrylonitrile obtained in(a) is added 0.5 g of sodium ethylate in 50 ml of ethanol. The reactionmixture is heated to reflux temperature, cooled to room temperature,poured into a mixture of dilute hydrochloric acid and ice, and stirredfor c. 1 hour. The precipitate is isolated by filtration, washed withwater and dried, affording the title compound in quantitative yield.Melting point: 149°-150° C.

Example P6 (Formulae, see Ex. P5) (a) Preparation of the intermediate3-(2,3-dichlorophenacylamino)acrylonitrile

2 g of 2,3-dichlorophenacylamine hydrochloride, 1 g of3-hydroxyacrylonitrile, sodium salt, and 20 ml of ethanol are heated for2 hours under reflux. The reaction mixture is concentrated byevaporation and the oily residue is purified by column chromatography(silica gel; elution with a 4:1 mixture of toluene/ethyl acetate),affording 3-(2,3-dichlorophenacylamino)acrylonitrile in the cis/transratio of 5:1. Melting point: 122°-125° C.

(b) Preparation of the final product4-(2,3-dichlorophenyl)-3-cyanopyrrole

4.2 g of the 3-(2,3-dichlorophenacylamino)acrylonitrile obtained in (a)are reacted in 50 ml of ethanol with 0.5 g of sodium ethylate asdescribed in Example P5 b), affording the title compound in quantitativeyield. Melting point: 150°-152° C.

Example P7 Preparation of ##STR20##4-(2,3-dichlorophenyl)-3-cyanopyrrole (a) Preparation of3-carbomethoxy-4-(2,3-dichlorophenyl)pyrrole

10.7 g of 2,3-dichlorophenacylamine hydrochloride and 6 g of methyl3-dimethylaminoacrylate are heated for 2 hours under reflux in 120 ml ofethanol. Then a solution of 4 g of sodium ethylate in 40 ml of ethanolis added dropwise and the reaction mixture is heated for another hourunder reflux. The reaction mixture is then concentrated by evaporationand the oily residue is purified by column chromatography (silica gel;elution with a 3:1 mixture of toluene/ethyl acetate. Melting point:205°-206° C.

(b) Preparation of the precursor4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid

3.2 g of the 3-carbomethoxy-4-(2,3-dichlorophenyl)pyrrole obtained in(a) and 40 ml of a 1:1 mixture of methanol and 5N HCl are stirred forhours at 70° C. After it has coled to room temperature, the reactionmixture is poured onto ice and extracted with ethyl acetate. The esterphase is in turn extracted with 10% sodium hydroxide solution. Theaqueous extract is washed twice with ethyl acetate, acidified withhydrochloric acid and extracted with ethyl acetate. The organic phase iswashed with water, dried over magnesium sulfate and filtered. Thefiltrate is concentrated by evaporation and the resultant4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid melts at 180°-182° C.

(c) Preparation of the final product:4-(2,3-dichlorophenyl)-3-cyanopyrrole

2.1 g of the free 4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acidobtained in (b) are dissolved in 30 ml of ethanol. The solution is madealkaline with concentrated ammonia and then evaporated to dryness. Theresidue is dissolved in 50 ml of ethanol. NH₃ gas is added (20 atm) tothis solution at room temperature in an autoclave and the reactionmixture is kept for 15 hours at 220° C. The reaction mixture, which hascooled to room temperature, is poured into ice/HCl, the precipitate isisolated by filtration and dried at 60° C. The resultant powder isheated with 17 g of polyphosphoric acid in an open vessel at 180° C.,the hot mixture is dropped onto ice, made alkaline with NaOH andextracted with ethyl acetate. The combined extracts are concentrated byevaporation and the residue is purified by column chromatography (silicagel; elution with a 4:1 mixture of toluene/ethyl acetate), affording4-(2,3-dichlorophenyl)-3-cyanopyrrole of m.p. 148°-150° C.

Example P8 Preparation of ##STR21##4-(2,3-dichlorophenyl)-3-cyanopyrrole (a) Preparation of3-formyl-4-(2,3-dichlorophenyl)pyrrole

5.4 g of 3-dimethylaminoacrolein, 3.2 g of 2,3-dichlorophenacylaminehydrochloride and 60 ml of ethanol are heated for 11/2 hours underreflux. Then a solution of sodium ethylate in ethanol (prepared from 1 gof sodium and 15 ml of ethanol) is added dropwise and the reactionmixture is heated under reflux for another 30 minutes. After it hascooled to room temperature, the reaction mixture is poured ontoice/water and neutralised with hydrochloric acid. The precipitate iswashed with water, dried in vacuo, and the dry residue is purified bycolumn chromatography (silica gel; elution with a 4:1 mixture oftoluene/ethyl acetate). M.p. 152°-154° C. IR (solid/KBr) in cm⁻¹ : 1655(CO). ¹ H-NMR (CDCl₃) in ppm: 7.0 (broad s, 1H); 7.3 (m, 2H); 9.66 (s,1H); 11.9 (s, 1H, H replaceable with D₂ O). Mass peak at 204. Thissubstance is novel, has fungicidal activity, and falls within the ambitof the invention.

(b) Preparation of hydroxyiminomethyl-4-(2,3-dichlorophenyl)pyrrole

5.0 g of the 3-formyl-4-(2,3-dichlorophenyl)pyrrole obtained in (a), 1.7g of hydroxylamine hydrochloride and 2.4 g of sodium acetate are stirredfor 3 hours at 80° C. in 80 ml of ethanol. After it has cooled to roomtemperature, the reaction mixture is poured onto ice and stirred for 30minutes. The precipitate is isolated by filtration, washed with waterand dried, affording 5.02 g of3-hydroxyiminomethyl-4-(2,3-dichlorophenyl)pyrrole as syn/anti mixtureof m.p. 158°-160° C. This substance is also novel, has fungicidalactivity and falls within the ambit of the invention.

(c) Preparation of the final product4-(2,3-dichlorophenyl)-3-cyanopyrrole

3.2 g of the 3-hydroxyiminomethyl-4-(2,3-dichlorophenyl)pyrrole obtainedin (b) are kept for 5 hours at c. 100° C. in 50 ml of acetic anhydride,then cooled to room temperature, poured into ice/NaOH, and the resultantmixture is stirred for 2 hours. The precipitate is dissolved in ethylacetate, washed with water, and the ester phase is dried over magnesiumsulfate. The residue is purified by column chromatography (silica gel;elution with a 4:1 mixture of toluene/ethyl acetate). Melting point:149°-151° C.

The compounds of formula I listed in Table 4 are also prepared bymethods corresponding to those described above. ##STR22##

                  TABLE 4                                                         ______________________________________                                        Com-                                                                          pound R.sub.n R.sub.1    R.sub.2     m.p. [°C.]                        ______________________________________                                        4.1   H       CN         H           120-123                                  4.2   3-Cl    CN         H           138-140                                  4.3   2,4-Cl.sub.2                                                                          CN         H           150-152                                  4.4   4-Cl    CN         H           153-155                                  4.5   4-F     CN         H           137-139                                  4.6   3-CH.sub.3                                                                            CN         H           109-111                                  4.7   3-F     CN         H           138-139                                  4.8   3-Br    CN         H           132-134                                  4.9   3-CF.sub.3                                                                            CN         H           87-89                                    4.10  2-Cl    CN         H           136-138                                  4.11  2,3-Cl.sub.2                                                                          CN         H           152-154                                  4.12  2,5-Cl.sub.2                                                                          CN         H           137-142                                  4.13  2-Br    CN         H           135-138                                  4.14  2,3-Cl.sub.2                                                                          COOCH.sub.3                                                                              H           205-206                                  4.15  2,3-Cl.sub.2                                                                          CHO        H           152-154                                  4.16  3-Cl    COOCH.sub.3                                                                              H           187-189                                  4.17  3,4-Cl.sub.2                                                                          COOCH.sub.3                                                                              H           183-186                                  4.18  2-Cl    COOCH.sub.3                                                                              H           198-200                                  4.19  2,3-Cl.sub.2                                                                          COOC.sub.3 H.sub.7 -i                                                                    H           153-156                                  4.20  2,3-Cl.sub.2                                                                          COOC.sub.2 H.sub.5                                                                       H           149-151                                  4.21  2,3-Cl.sub.2                                                                          CN         CH.sub.2 CH.sub. 2 CN                                4.22  2,3-Cl.sub.2                                                                          CN         CH.sub.2 CH.sub.2 COOCH.sub.3                        ______________________________________                                    

The described process, including all partial steps, constitutes anobject of this invention.

What is claimed is:
 1. A compound of the formula IV ##STR23## wherein R₁is CN or CHO, R₂ is hydrogen, R is chlorine and n is
 2. 2. A compound offormula IV according to claim 1, wherein R₁ is cyano, R₂ is hydrogen, Ris chlorine and n is 2.